Download 10/29/2014 Psychedelic Drugs Alter Perception and Cognition

10/29/2014
Psychedelic Drugs Alter Perception and Cognition
Psychedelics are often taken to intentionally alter subjective states of consciousness
Psychedelics are often taken to intentionally alter subjective states of consciousness
rather than for a direct reinforcing effect. Not all psychedelic “trips” are positive –
humans may intentionally seek various types of experiences.
Psychedelic derived from Greek language
psyche “soul, mind” delein “to manifest”
Psychedelic Drugs Lack Direct Reinforcing Effects Versus Other Drugs
(Cocaine, Amphetamines, Opiods)
Animals are less likely to self‐administer psychedelic drugs and may even avoid them.
Meh…
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Psychedelic versus Hallucinogenic Nomenclature
True hallucinations
True hallucinations
Perceptions occurring in the absence of appropriate stimuli
Psychedelic substance induced “hallucinations”
Altered sensory perception that may be compared to dreaming, meditation, or a religious experience
Psychedelic versus Hallucinogenic Nomenclature
Schizophrenic hallucinations
• Generally auditory
• Often unpleasant and threatening
• Derived from user’s internal mental state, not from external environment
Drug‐induced “hallucinations”
• Mostly visual
• Generally considered pleasant or neutral
• Involve distortions of environmental stimuli
People with schizophrenia who have taken LSD acknowledge that it is different from a psychotic experience.
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Pharmacology of Psychedelic Drugs
Most act through agonizing serotonin receptors ‐ primarily 5
Most act through agonizing serotonin receptors primarily 5‐HT
HT2A
Lysergic acid diethylamide (LSD)
Psilocybin (psilocin active metabolite)
Mescaline
Dimethyltryptamine (DMT)
serotonin
5‐hydroxytryptamine (5‐HT)
Structural Comparisons of Serotonin and 5‐HT2A Agonists
O
N
serotonin
5‐hydroxytryptamine (5‐HT)
N
H
N
H
psilocin
LSD
N
N
H
DMT
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Lysergic Acid Diethylamide (LSD) – The Prototypical Psychedelic
Semi‐synthetic compound from ergotamine, produced by the ergot fungus.
First synthesis of LSD – 1938 by Albert Hoffman
O
HO
N
H
N
H
ergotamine
lysergic acid
lysergic acid diethylamide (LSD)
Lysergic Acid Diethylamide (LSD) – The Prototypical Psychedelic
While seeking compounds that would act as respiratory and circulatory stimulants (analeptics), g
p
p
y
y
(
p ),
in 1943 at Sandoz, Hoffman inadvertently absorbed LSD through the skin.
Hoffman (1906 – 2008) 4
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Lysergic Acid Diethylamide (LSD) – The Prototypical Psychedelic
Albert Hoffman, 1943 after accidental exposure to LSD:
... affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant intoxicated‐like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense,
i
di
h
i hi
k l id
kaleidoscopic play of colors. After about two i l
f l
Af
b
hours this condition faded away.
Lysergic Acid Diethylamide (LSD) – “Bicycle Day”
Hoffman then intentionally ingested 0.25 mg (250 mcg) LSD, predicting it as the threshold dose. (actual threshold dose = 25 mcg) Initial feelings of anxiety and terror with minimal physiological signs of toxicity (dilated pupils) Fear eventually converted to enjoyment. “Bicycle day” named after his infamous ride home from the laboratory.
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Lysergic Acid Diethylamide (LSD) – “Bicycle Day”
Albert Hoffman, 1943, after intentional administration of LSD:
... little by little I could begin to enjoy the unprecedented colors and plays of shapes that persisted behind my closed eyes. Kaleidoscopic, fantastic images surged in on me, alternating, variegated, opening and then closing themselves in circles and spirals, exploding in colored fountains, rearranging and hybridizing themselves in constant flux ...
Lysergic Acid Diethylamide Early Use
Early 1950’s –
arly 950 s mid
mid 1970’s
970 s
1000 scientific papers published on its use in psychotherapy
1950s – 1970s
CIA performed studies with LSD, administering it to mental patients, prisoners, and drug addicts often without subjects’ knowledge or consent (Project MKULtra)
1966
LSD listed as Schedule I
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LSD Dose is Extremely Low
25 mcg (0.025 mg)
g (
g) threshold dose for noticeable effects
Typical doses 100 – 300 mcg (0.1 – 0.3 mg)
Generally administered orally via blotter paper or a dilute solution
LSD is light sensitive thus stored in dark bottles or wrapped in foil
LSD Pharmacokinetics
Ab
Absorption
ti
Occurs within 60 minutes after oral administration
Peak blood levels ca. 3 hours
Distribution
Rapid and efficient – readily crosses BBB
Accumulates in liver where it is metabolized
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LSD Pharmacokinetics Continued
Half‐life
LSD half life is 3.5‐5 hours though effects can last from 6‐12 hours
Metabolism
Oxidative metabolites and dealkylated metabolites
Elimination
2‐oxo‐3‐hydroxy‐LSD is major urine metabolite
LSD Tolerance
Tolerance to effects can develop in humans after a few moderate daily doses
though tolerance is generally lost after several days of abstaining from the drug.
Cross‐tolerance can develop between:
• LSD
• mescaline
• psilocybin
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LSD Toxicity
No documented human deaths from overdose of LSD
LD50 varies by species – primates have been dosed up to 1 mg/kg IV High therapeutic index drug (TI >100)
Low dose results in desired effects (100‐300 mcg)
Toxic dose is substantially higher (Some estimates at 14 mg, potentially higher) LSD Physiological Effects
Mild sympathomimetic
y p
• Dilated pupils
• Light to moderate elevation in heart rate
• Light to moderate elevation in blood pressure
Sympathomimetic drugs mimic the effects of catecholamine neurotransmitters
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LSD Psychological Effects
Altered perception, thinking, emotion, arousal and self‐image
p
p
,
g,
,
g
• Enhanced sensory perception ‐ visual, audio, tactile
• Distorted sense of time (cycling may occur)
• Synesthesia – senses can interconvert (e.g. sounds become images)
Descriptive information on psychedelic experience:
http://en.wikipedia.org/wiki/Psychedelic_experience
LSD Adverse Events
Acute negative effects based on dose, individual, set and setting
Confusion anxiety panic dissociative state or psychotic reaction can occur
Confusion, anxiety, panic, dissociative state, or psychotic reaction can occur
Flashbacks
Short‐term, non‐distressing, spontaneous, recurrent, reversible and benign condition accompanied by a pleasant effect
Hallucinogen persisting perception disorder (HPPD)
Long‐term, distressing, spontaneous, recurrent, pervasive, slowly reversible or irreversible non‐
benign condition accompanied by an unpleasant dysphoric affect
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Physical Dependence on LSD Does Not Develop Even When Drug Used Repeatedly for Prolonged Time Periods
Heavy LSD users indicate they may tire of the drug, have no further need for it, or have “had enough” http://en.wikipedia.org/wiki/Lysergic_acid_diethylamide
LSD Analog Present in Nature
O
H2 N
N
H
lysergamide / ergine / LSA
Schedule III (LSD precursor)
depressant
N
H
morning glory seeds
Hawaiian baby woodrose seeds
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LSD Analogs in Medicine
ergotamine combined with caffeine
migraine treatment
ergometrine
OB use: facilitate placenta delivery
and prevent bleeding after childbirth
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